Inherited mutations of collagen VI genes cause two main skeletal muscle diseases, Bethlem myopathy (BM, Online Mendelian Inheritance in Man [OMIM] 158810), and Ullrich congenital muscular dystrophy (UCMD, OMIM 254090).
BM is an autosomal dominant disorder characterized by slowly progressive axial and proximal muscle weakness with flexion finger contracture. (Bethlem and Wijngaarden. Brain 1976; 99: 91-100; Merlini et al. Neuromuscul Disord 1994; 4: 503-11). It presents intrafamiliar variability and different clinical onset from prenatal to mid-adulthood. Prenatal onset is characterized by decreased fetal movements; neonatal onset by hypotonia or torticollis; early-childhood onset by delayed motor milestones, muscle weakness and contractures; and adult onset by proximal weakness, achiIles tendon and fingers contractures. The condition is usually mild and slowly progressive with some affected individuals over 50 years of age needing aids for outdoors mobility. (Pepe et al. Biochem Biophys Res Commun 1999; 258: 802-07. De Visser et al. Muscle Nerve 1992; 15: 591-96). Cardiac function is usually normal.
UCMD is an autosomal recessive disorder characterized by congenital muscle weakness with joint contractures and coexisting distal joint hyperlaxity. (Ullrich. Z. Ges. Neurol. Psychiatr. 1930; 126: 171-201. Camacho Vanegas et al. Proc Natl Acad Sci USA 2001; 98: 7516-21.) The presentation is usually at birth with hypotonia, congenital hip dislocation, prominent calcanei, and a transient kyphotic deformity. Motor milestones are delayed and most of the children never acquire the ability to walk independently. Follicular hyperkeratosis over the extensor surfaces of upper and lower limbs and keloid and cigarette paper scar formation are common. Axial muscle involvement is severe resulting in progressive scoliosis with spine rigidity. Early and severe respiratory involvement may require artificial ventilatory support in the first or second decade of life. The subjects affected by UCMD have a normal intelligence, and MRI shows a normal brain development. Patients with recessive or de novo heterozygous mutations usually have a classic severe phenotype, although they may occasionally present a milder Bethlem-type disease. (Pan et al. Am J Hum Genet. 2003; 73: 355-69. Baker et al. Hum Mol Genet. 2005; 14: 279-93. Demir et al. Am J Hum Genet. 2002; 70: 1446-58.) In some patients with the UCMD phenotype, mutations of collagen VI genes were excluded, suggesting genetic heterogeneity even for this condition. (Pan et al. Am J Hum Genet. 2003; 73: 355-69).
Recently, it was shown that mice lacking collagen VI due to targeted inactivation of the Col6a1 gene have a latent mitochondrial defect caused by inappropriate opening of the permeability transition pore (PTP), an inner membrane channel that plays a role in several forms of cell death and can be desensitized by cyclosporin A. (Irwin et al. Nat Genet. 2003; 35: 267-71. Bernardi et al. FEBS J 2006; 273: 2077-99.) This finding was further exploited in vivo, and led to successful therapeutic intervention in the mouse model. Establishing whether mitochondria are involved in the pathogenesis of the genetically and clinically heterogeneous UCMD represented a major chaIlenge, which was the main hurdle to the therapeutic application in humans of the regimen defined in the mouse model. This chaIlenge has now been overcome. Furthermore, the present inventors have been able to demonstrate that latent mitochondrial defects present in cells of UCMD patients and resulting elevated rates of apoptosis can be inhibited by non-immunosuppressive cyclosporin A derivatives such as [D-MeAla]3-[EtVal]4-CsA. Consequently, the present invention provides for a new method for inhibiting apoptosis of muscle cells of patients suffering from UCMD and a new method of treatment of this disease in these patients using a non-immunosuppressive derivative of cylosporin A, preferably [D-MeAla]3-[EtVal]4-CsA. No effective method for treating UCMD is presently available. Hence, there is a need for new therapeutic approaches such as that described herein. The present inventors were also able to uncover a similar mitochondrial defect in BM patients that was sensitive to cyclosporin A. Hence, the new method of treatment disclosed herein for UCMD patients is also applicable for the treatment of BM patients.